Cytomegalovirus (CMV) is a DNA virus belonging to the herpes
virus group. The infection from this virus is increasing in the immune
compromised patients, especially AIDS or organ transplant recipients.
Nevertheless, the skin lesion is uncommon. We present two cases of
atypical cutaneous CMV infection.

The first case was a 66 year-old Thai woman with overlapping
syndrome, on treatment with multiple immune suppressants. She
presented with high grade fever and asymptomatic purpuric papules
and pustules on her forearms and legs. Laboratory investigations
showed bicytopenia from complete blood count. Chest radiography
and high-resolution computed tomography of the chest revealed lung
nodules.

The second case was a 49-year-old Thai woman with Systemic
Lupus Erythematosus (SLE) and obtained multiple immune
suppressants. She presented with fever and multiple erythematous
papules with ulcers of the extremities and trunk. Basic laboratory
investigations were normal.

The skin biopsies from both cases showed perivascular infiltration
with inflammatory cells and numerous large round eosinophilic
intranuclear inclusion bodies (owl's eye appearance) in the dermis.
The CMV antigen stained the cytoplasm of owl's eye cells.
Further investigations presented high level CMV viral load in both
cases. The diagnosis CMV infection was made.

In conclusion, we presented the cases with cutaneous CMV
infection in immune compromised host. This group of patients is
susceptible to variety of infections and presented with atypical
manifestations. Cutaneous manifestations with skin biopsy in some
cases may play a major role for the correct diagnosis and prompt
treatment.

Cytomegalovirus (CMV) is a DNA virus belonging to the
herpesviridae family. It is a common opportunistic infection in
fetus, allograft and bone marrow transplant recipients and AIDS [1]. The infection was detected close to 100% in developing
countries [1, 2]. The transmission occurs via body fluids (saliva,
urine, blood, semen, vaginal secretion, breast milk) and also via
transplant organs [2]. In the primary infection, CMV can infect
many cell types and causes viremia, using blood leukocytes
as transport medium [2, 3]. After the primary infection, CMV
stayed latently lifelong in the hosts and rarely causes diseases in
immunocompetent individuals [3].

Physical examination revealed 38.7oC body temperature.
There were multiple ill-defined erythematous purpuric patches
and pustules on the forearms and legs (Figure 1). Other
examinations were unremarkable.

The skin biopsy from the skin lesion on the forearm
showed superficial and deep perivascular and interstitial
infiltrations composed of predominantly neutrophils, nuclear
dusts and extravasated red blood cells. There were vascular
walls destruction and fibrinoid depositions. Large cells with
eosinophilic intracytoplasmic and intranuclear inclusion bodies
(owl's eye cells) were observed in the vascular endothelium
(Figure 2). The immunohistochemistry for CMV antigen
highlighted in the cytoplasm of these owl’s eye cells (Figure 3).

Further laboratory investigations revealed anemia,
lymphopenia and high CMV viral load (2,418,532 copies/ml).
Chest x-ray showed reticulonodular infiltration in both lungs.
The retinal examination from an opthalmologist was normal.

She was diagnosed as active CMV infection. The treatment

Figure 1: Clinical appearances of Case 1 presenting as purpuric patches
and pustules on right thigh.

Figure 3:The immunohistochemistry for CMV antigen highlighted in
the cytoplasm of these owl’s eye cells.

was started with intravenous ganciclovir. After 1 week of the
treatment, her condition turned worse. She still had high grade
fever. Acid fast bacilli were found from the sputum examination
which was compatible with pulmonary tuberculosis. She
developed dyspnea and passed away from respiratory failure
before starting the anti-tuberculous agents..

Case 2

A 49-year-old woman presented with high grade fever and
asymptomatic skin rashes for 3 weeks. She had underlying
diseases as systemic lupus erythematosus (SLE) which was well
controlled with mycophenolate mofetil 2 g/d, prednisolone 40
mg/d and chloroquine 250 mg/d.

Physical examinations showed 38.8oC body temperature.
There were multiple well-defined erythematous crusted papules
on her right arm, right forearm and abdominal wall with a
solitary ill-defined erythematous papule with shallow ulcer and
pustules on the right elbow (Figure 4, 5). Other examinations
were unremarkable.

The skin biopsy form the ulcer revealed dense superficial
and deep perivascular and interstitial infiltration composed of
lymphocytes and histiocytes. There were vascular wall destruction
with fibrinoid deposition and numerous large round cells with
eosinophilic intranuclear inclusion bodies (owl's eye cells) in the
endothelial cells (Figure 6). The immunohistochemistry for CMV
antigen highlighted in the cytoplasm of owl's eye cells (Figure 7).

Further laboratory investigations showed anemia,
lymphopenia and also high CMV viral load (2,624,532 copies/
ml). The retinal examination from an opthalmologist was normal.

She was diagnosed as active CMV infection. The treatment
was started with intravenous ganciclovir. After 8 weeks of the
treatment, the lesions were resolved without any complication.

Discussion

CMV infection causes various dermatologic and systemic
disorders but usually asymptomatic in immunocompetent hosts
[3]. The most common clinical presentation is a mononucleosislike
syndrome resemble to EBV infection [2, 4].

In immunocompromised host, CMV infection presents as
a wide variety of manifestations depending on the degree of
immunosuppression which is a major cause of morbidity and
mortality.. This group of patients usually acquires disseminated
CMV disease involving many organs, resulting to chorioretinitis,
pneumonitis, gastrointestinal, Central Nervous System (CNS),
renal, bone marrow and endocrine abnormalities [2, 5].

The typical histopathology of tissues infected with
cytomegalovirus shows characteristic cells with intranuclear
and intracytoplasmic inclusion bodies (owl's eye appearance)
which was only limited to fully developed lesions [6, 8]. In early
infection, the initial cellular change is cell enlargement with
enlarged basophilic nucleus and prominent nucleolus. Then
the cell continues to enlarge and the cytoplasm has smudged,
amphophilic, bubbly quality. The fully developed change shows
basophilic intranuclear and intracytoplasmic inclusion bodies.
While the CMV infection resolves, the cell including the nucleus
shrinks [6, 8]. The affected cells are mostly mesenchymal cells,
especially endothelial cells. Fibroblasts, inflammatory cells, and
rarely epithelial cells are less commonly affected [6, 8, 9].

Figure 7:The immunohistochemistry for CMV antigen highlighted in
the cytoplasm of these owl's eye cells.

vasculitis, eccrine squamous syringometaplasia, and neuritis
[10-12]. The diagnosis of CMV vasculitis is made when there are
evidence of vascular destruction (vessel wall damage, necrosis
and luminal obstruction). CMV associated-vasculitis can occur
in the internal organs, especially GI tract and central nervous
system [13]. The vascular injury can be caused by either direct
endothelial damage by virus, which usually shows the typical
inclusion bodies in the endothelial cells or via induction of
immune-mediated hypersensitivity [10, 13, 14]. Furthermore,
cytomegalovirus neuritis was diagnosed by demonstrate the
CMV inclusion bodies in the Schwann cells [12].

In addition to CMV infection in AIDs and transplant recipients,
there were many reports of the association of CMV infection and
connective tissue diseases.

In SLE, the increased risk of infections due to the prolonged
use of immunosuppressants was mentioned. Ramos-Casals M, et
al, showed that CMV was the most common viral infection in SLE
[15]. CMV antibodies were detected in nearly 50% of SLE cases
who presented with acute viral infection and the majority of the
cases were Asian. [15]

The association of CMV infection and SLE is still unclear
but may involve many factors. Active SLE induces immune
reactivation which induces proliferation of immune cells,
resulting in proliferation of latent CMV in the cells. In addition,
immunosuppressive treatments may also allow the reactivation
of latent virus [16-18]. In the contrary, CMV infection can also
trigger the development and the flare of SLE [16, 17]. This group
of patients presented with acute CMV infection and positive IgM
anti CMV antibodies prior to the diagnosis of SLE [16-19]. The
mechanism of CMV induced autoimmunity had not been fully
clarified. The possible mechanism is the cross-reactivity between
T-cell and CMV antigens in susceptible individual. [19-20]

CMV has been reported as a triggering factor of vascular
damage in systemic sclerosis.21 Moreover, CMV DNA specific
antigens were detected in synovial tissue and fluid from
rheumatoid arthritis joints in 10-50% of the patients, but the role
of involving the disease is still unclear. [21-25]

The clinical manifestations of active CMV infection can
also mimic the active SLE flare as seen in our cases with the
presenting symptoms of fever, skin lesions resemble cutaneous
vasculitis, lymphopenia and anemia [18]. The diagnosis of CMV
infection was confirmed by the feature of CMV vasculitis in
the skin biopsies and the elevated serum CMV viral load. The
causative factors of CMV infection in our cases may be from
prolonged immunosuppressants reactivated the latent CMV
infection.

The first line treatment for CMV infection is intravenous
ganciclovir, while oral valganciclovir is preferred for prophylaxis
and preemptive therapy [26-28]. The second-line treatment is
foscarnet which is limited to be used in ganciclovir-resistant CMV
infection or in patients contraindicated to use ganciclovir. The
third agent is cidoforvir which is limited to be used due to the
presence of poor bioavailability and nephrotoxicity. [26]

In conclusion, we reported two cases of active CMV infections
who presented with non-specific skin lesions. Both cases had
underlying connective tissue diseases, controlled with multiple
immunosuppressants. The clinical presentation of CMV infection
can mimic flare of the underlying diseases. The careful physical
examinations and proper investigations are keys for the diagnosis
and prompt management.